Glycogen synthesis is the major fate of a glucose load in healthy humans and abnormalities in glycogen synthesis is the major factor responsible for insulin resistance in type Il diabetes mellitus. The overall goal of this proposal is the application of NMR spectroscopic techniques in conjunction with GC-MS and radioisotopic techniques to investigate the regulation of liver and muscle glycogen metabolism in healthy humans and their respective roles in the pathogenesis of insulin resistance and glucose intolerance in diabetic humans. During the tenure of this grant we will examine: (l) The relative contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in healthy humans during the first 6-10 hours of a fast, (2) The respective roles of hepatic and muscle glycogen synthesis as well as suppression of hepatic glucose production following a mixed meal in causing postprandial hyperglycemia in non insulin dependent diabetes mellitus, (3) Whether liver glycogen synthesis is altered in type l diabetic subjects throughout the course of a 24 hour period in which 3 mixed meals are ingested, (4) Under conditions of a hyperglycemic-hyperinsulinemic clamp, the impact of type l and type II diabetes on net rates and pathways (direct and indirect) of hepatic glycogen synthesis as well as the role of glucagon on the regulation of these fluxes, (5) Whether defects in glucose transport/phosphorylation are primary or secondary in the pathogenesis of type Il diabetes mellitus and if they are reversible with an intensive 12 week aerobic exercise program and (6) The effects of an intensive bout of exercise on glucose transport/phosphorylation and glycogen synthase activity during the rapid insulin-independent phase of glycogen repletion as well as the slower insulin-dependent phase in insulin resistant offspring of NIDDM patients. The results from these studies should: (l) provide new insights into the regulation of liver and muscle glycogen metabolism in healthy humans during fed and fasted states, (2) quantify the relative roles of liver and muscle in causing postprandial hyperglycemia in NIDDM, (3) identify alterations in hepatic glycogen synthesis that occur in type l diabetes mellitus which might be an important predisposing factor in the development of severe hypoglycemia, (4) assist with the search for candidate gene(s) for NIDDM by determining whether glucose transport/phosphorylation is a primary defect in its pathogenesis and (5) elucidate the mechanism by which acute and chronic exercise training reverses insulin resistance which has important therapeutic implications for treatment of patients with NIDDM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049230-04
Application #
2654535
Study Section
Nutrition Study Section (NTN)
Program Officer
Laughlin, Maren R
Project Start
1995-02-01
Project End
2000-01-31
Budget Start
1998-03-17
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Madiraju, Anila K; Qiu, Yang; Perry, Rachel J et al. (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24:1384-1394
Petersen, Max C; Vatner, Daniel F; Shulman, Gerald I (2017) Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol 13:572-587
von Loeffelholz, Christian; Lieske, Stefanie; Neuschäfer-Rube, Frank et al. (2017) The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism. Hepatology 66:616-630
Tricò, Domenico; Di Sessa, Anna; Caprio, Sonia et al. (2017) Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota? Antioxid Redox Signal :
Perry, Rachel J; Peng, Liang; Cline, Gary W et al. (2017) A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo. Cell Metab 25:749-756
Goffredo, Martina; Caprio, Sonia; Feldstein, Ariel E et al. (2016) Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 63:117-25
Hershkop, Karen; Besor, Omri; Santoro, Nicola et al. (2016) Adipose Insulin Resistance in Obese Adolescents Across the Spectrum of Glucose Tolerance. J Clin Endocrinol Metab 101:2423-31
Johnson, Matthew L; Distelmaier, Klaus; Lanza, Ian R et al. (2016) Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults. Diabetes 65:74-84
Petersen, Kitt Falk; Befroy, Douglas E; Dufour, Sylvie et al. (2016) Assessment of Hepatic Mitochondrial Oxidation and Pyruvate Cycling in NAFLD by (13)C Magnetic Resonance Spectroscopy. Cell Metab 24:167-71
Kursawe, Romy; Dixit, Vishwa D; Scherer, Philipp E et al. (2016) A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 65:610-8

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